JP2016527006A5 - - Google Patents

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Publication number: JP2016527006A5
Authority: JP; Japan
Prior art keywords: hydroxy; bone; methyl; oxopyrrolidin; difluoro
Prior art date: 2014-07-18
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Pending

Application number

JP2016527117A

Other languages

English (en)

Japanese (ja)

Other versions

JP2016527006A (ja

Filing date

2014-07-18

Publication date

2017-08-31

2014-07-18 Application filed filed Critical

2014-07-18 Priority claimed from PCT/US2014/047138 external-priority patent/WO2015009991A2/en

2016-09-08 Publication of JP2016527006A publication Critical patent/JP2016527006A/ja

2017-08-31 Publication of JP2016527006A5 publication Critical patent/JP2016527006A5/ja

Status Pending legal-status Critical Current

Links

210000000988 Bone and Bones Anatomy 0.000 claims description 131
239000000203 mixture Substances 0.000 claims description 87
QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 43
239000003795 chemical substances by application Substances 0.000 claims description 39
239000001506 calcium phosphate Substances 0.000 claims description 27
239000003814 drug Substances 0.000 claims description 25
229910000389 calcium phosphate Inorganic materials 0.000 claims description 23
235000011010 calcium phosphates Nutrition 0.000 claims description 23
239000004568 cement Substances 0.000 claims description 23
210000002805 Bone Matrix Anatomy 0.000 claims description 22
229940079593 drugs Drugs 0.000 claims description 20
239000000556 agonist Substances 0.000 claims description 17
210000002997 Osteoclasts Anatomy 0.000 claims description 9
210000000963 osteoblast Anatomy 0.000 claims description 9
230000000790 osteoblast Effects 0.000 claims description 9
230000002148 osteoclast Effects 0.000 claims description 9
239000000919 ceramic Substances 0.000 claims description 8
150000003839 salts Chemical class 0.000 claims description 7
239000011780 sodium chloride Substances 0.000 claims description 7
229940046008 Vitamin D Drugs 0.000 claims description 6
229930003316 Vitamin D Natural products 0.000 claims description 6
239000003112 inhibitor Substances 0.000 claims description 6
230000002401 inhibitory effect Effects 0.000 claims description 6
235000019166 vitamin D Nutrition 0.000 claims description 6
239000011710 vitamin D Substances 0.000 claims description 6
150000003710 vitamin D derivatives Chemical class 0.000 claims description 6
229940112871 Bisphosphonate drugs affecting bone structure and mineralization Drugs 0.000 claims description 5
102000003982 Parathyroid hormone Human genes 0.000 claims description 5
108090000445 Parathyroid hormone Proteins 0.000 claims description 5
XXUZFRDUEGQHOV-UHFFFAOYSA-J Strontium ranelate Chemical compound [Sr+2].[Sr+2].[O-]C(=O)CN(CC([O-])=O)C=1SC(C([O-])=O)=C(CC([O-])=O)C=1C#N XXUZFRDUEGQHOV-UHFFFAOYSA-J 0.000 claims description 5
150000004663 bisphosphonates Chemical class 0.000 claims description 5
230000037182 bone density Effects 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 5
239000002834 estrogen receptor modulator Substances 0.000 claims description 5
239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 5
239000000199 parathyroid hormone Substances 0.000 claims description 5
229960001319 parathyroid hormone Drugs 0.000 claims description 5
239000000849 selective androgen receptor modulator Substances 0.000 claims description 5
239000007787 solid Substances 0.000 claims description 5
229940079488 strontium ranelate Drugs 0.000 claims description 5
NEFBYIFKOOEVPA-UHFFFAOYSA-K Dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims description 4
235000019739 Dicalciumphosphate Nutrition 0.000 claims description 4
239000000515 collagen sponge Substances 0.000 claims description 4
229910000390 dicalcium phosphate Inorganic materials 0.000 claims description 4
229940038472 dicalcium phosphate Drugs 0.000 claims description 4
229910052588 hydroxylapatite Inorganic materials 0.000 claims description 4
FDFYYWMHPJTGEO-UHFFFAOYSA-K tetracalcium;phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O FDFYYWMHPJTGEO-UHFFFAOYSA-K 0.000 claims description 4
XEYBRNLFEZDVAW-ARSRFYASSA-N (5Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxyoct-1-en-1-yl]-5-oxocyclopentyl]hept-5-enoic acid Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 claims description 3
102000007350 Bone Morphogenetic Proteins Human genes 0.000 claims description 3
108010007726 Bone Morphogenetic Proteins Proteins 0.000 claims description 3
GXJABQQUPOEUTA-RDJZCZTQSA-N Bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 claims description 3
102000004171 Cathepsin K Human genes 0.000 claims description 3
108090000625 Cathepsin K Proteins 0.000 claims description 3
108010047852 Integrin alphaVbeta3 Proteins 0.000 claims description 3
102000010780 Platelet-Derived Growth Factor Human genes 0.000 claims description 3
108010038512 Platelet-Derived Growth Factor Proteins 0.000 claims description 3
102000014128 RANK Ligand Human genes 0.000 claims description 3
108010025832 RANK Ligand Proteins 0.000 claims description 3
239000012190 activator Substances 0.000 claims description 3
239000000362 adenosine triphosphatase inhibitor Substances 0.000 claims description 3
229960000711 alprostadil Drugs 0.000 claims description 3
239000003098 androgen Substances 0.000 claims description 3
102000015735 beta Catenin Human genes 0.000 claims description 3
108060000903 beta Catenin Proteins 0.000 claims description 3
210000002449 bone cell Anatomy 0.000 claims description 3
229960001467 bortezomib Drugs 0.000 claims description 3
229960002986 dinoprostone Drugs 0.000 claims description 3
239000000262 estrogen Substances 0.000 claims description 3
GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 claims description 3
239000002464 receptor antagonist Substances 0.000 claims description 3
230000011664 signaling Effects 0.000 claims description 3
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 180
QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 82
MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 78
WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 68
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 64
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 50
MNWFXJYAOYHMED-UHFFFAOYSA-N Heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 40
239000005711 Benzoic acid Substances 0.000 description 34
125000000217 alkyl group Chemical group 0.000 description 34
235000010233 benzoic acid Nutrition 0.000 description 34
-1 7-((R) -3,3-difluoro-5-((S, E) -3-hydroxy-7-phenylhept-1-en-1-yl) -2-oxopyrrolidin-1-yl) heptane Chemical compound 0.000 description 30
WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 22
229910052799 carbon Inorganic materials 0.000 description 20
125000006238 prop-1-en-1-yl group Chemical compound [H]\C(*)=C(/[H])C([H])([H])[H] 0.000 description 20
229910052739 hydrogen Inorganic materials 0.000 description 18
125000003545 alkoxy group Chemical group 0.000 description 14
125000001188 haloalkyl group Chemical group 0.000 description 14
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
125000001424 substituent group Chemical group 0.000 description 12
125000004093 cyano group Chemical group *C#N 0.000 description 10
125000004438 haloalkoxy group Chemical group 0.000 description 10
229910052736 halogen Inorganic materials 0.000 description 10
150000002367 halogens Chemical class 0.000 description 10
239000002253 acid Substances 0.000 description 8
125000004450 alkenylene group Chemical group 0.000 description 8
125000002947 alkylene group Chemical group 0.000 description 8
125000004419 alkynylene group Chemical group 0.000 description 8
125000003118 aryl group Chemical group 0.000 description 8
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
229910052717 sulfur Inorganic materials 0.000 description 8
125000001153 fluoro group Chemical group F* 0.000 description 6
125000001072 heteroaryl group Chemical group 0.000 description 6
OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 4
XRASPMIURGNCCH-UHFFFAOYSA-N Zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
125000003342 alkenyl group Chemical group 0.000 description 4
125000004448 alkyl carbonyl group Chemical group 0.000 description 4
125000000304 alkynyl group Chemical group 0.000 description 4
239000000730 antalgic agent Substances 0.000 description 4
239000003242 anti bacterial agent Substances 0.000 description 4
239000002260 anti-inflammatory agent Substances 0.000 description 4
239000002246 antineoplastic agent Substances 0.000 description 4
125000000753 cycloalkyl group Chemical group 0.000 description 4
125000000262 haloalkenyl group Chemical group 0.000 description 4
125000000232 haloalkynyl group Chemical group 0.000 description 4
229910052760 oxygen Inorganic materials 0.000 description 4
125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 4
229960004276 zoledronic acid Drugs 0.000 description 4
FJLGEFLZQAZZCD-JUFISIKESA-N (3S,5R)-fluvastatin Chemical compound C12=CC=CC=C2N(C(C)C)C(\C=C\[C@H](O)C[C@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 FJLGEFLZQAZZCD-JUFISIKESA-N 0.000 description 2
125000004214 1-pyrrolidinyl group Chemical compound [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
MVCFMJVPAKMEFL-WFJXPABVSA-N 4-[2-[(5R)-3,3-difluoro-5-[(E,3R)-3-hydroxyoct-1-enyl]-2-oxopyrrolidin-1-yl]ethyl]benzoic acid Chemical compound CCCCC[C@@H](O)\C=C\[C@H]1CC(F)(F)C(=O)N1CCC1=CC=C(C(O)=O)C=C1 MVCFMJVPAKMEFL-WFJXPABVSA-N 0.000 description 2
BMBNIHYSJNFUPW-PNVKXUSSSA-N 4-[2-[(5R)-3,3-difluoro-5-[(E,3S)-3-hydroxy-7-phenylhept-1-enyl]-2-oxopyrrolidin-1-yl]ethyl]benzoic acid Chemical compound C([C@H](O)\C=C\[C@@H]1N(C(=O)C(F)(F)C1)CCC=1C=CC(=CC=1)C(O)=O)CCCC1=CC=CC=C1 BMBNIHYSJNFUPW-PNVKXUSSSA-N 0.000 description 2
MVCFMJVPAKMEFL-QTYXSNHHSA-N 4-[2-[(5R)-3,3-difluoro-5-[(E,3S)-3-hydroxyoct-1-enyl]-2-oxopyrrolidin-1-yl]ethyl]benzoic acid Chemical compound CCCCC[C@H](O)\C=C\[C@H]1CC(F)(F)C(=O)N1CCC1=CC=C(C(O)=O)C=C1 MVCFMJVPAKMEFL-QTYXSNHHSA-N 0.000 description 2
AWMIWDCKBUKDKJ-XGRPXUFSSA-N 4-[2-[(5R)-3,3-difluoro-5-[(E,3S,4S)-3-hydroxy-4-methyl-7-phenylhept-1-enyl]-2-oxopyrrolidin-1-yl]ethyl]benzoic acid Chemical compound C([C@H](C)[C@H](O)\C=C\[C@@H]1N(C(=O)C(F)(F)C1)CCC=1C=CC(=CC=1)C(O)=O)CCC1=CC=CC=C1 AWMIWDCKBUKDKJ-XGRPXUFSSA-N 0.000 description 2
PLPPXVWLEPOTQM-KNUMWTCJSA-N 4-[2-[(5R)-3,3-difluoro-5-[(E,3S,4S)-3-hydroxy-4-methyloct-1-enyl]-2-oxopyrrolidin-1-yl]ethyl]benzoic acid Chemical compound CCCC[C@H](C)[C@H](O)\C=C\[C@H]1CC(F)(F)C(=O)N1CCC1=CC=C(C(O)=O)C=C1 PLPPXVWLEPOTQM-KNUMWTCJSA-N 0.000 description 2
ZXECFDRPIPRVFB-GWCPOKRPSA-N 5-[3-[(2R)-2-[(E,3R,4R)-3-hydroxy-4-methyl-6-phenylhex-1-enyl]-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@@H](C)[C@@H](O)\C=C\[C@@H]1N(C(=O)CC1)CCCC=1SC(=CC=1)C(O)=O)CC1=CC=CC=C1 ZXECFDRPIPRVFB-GWCPOKRPSA-N 0.000 description 2
ATRZOBDJGRNPEF-YFZNZOHDSA-N 5-[3-[(2R)-2-[(E,3R,4R)-3-hydroxy-4-methyl-8-phenyloct-1-enyl]-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@@H](C)[C@@H](O)\C=C\[C@@H]1N(C(=O)CC1)CCCC=1SC(=CC=1)C(O)=O)CCCC1=CC=CC=C1 ATRZOBDJGRNPEF-YFZNZOHDSA-N 0.000 description 2
ZXECFDRPIPRVFB-BLRXGEEQSA-N 5-[3-[(2R)-2-[(E,3R,4S)-3-hydroxy-4-methyl-6-phenylhex-1-enyl]-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@H](C)[C@@H](O)\C=C\[C@@H]1N(C(=O)CC1)CCCC=1SC(=CC=1)C(O)=O)CC1=CC=CC=C1 ZXECFDRPIPRVFB-BLRXGEEQSA-N 0.000 description 2
ATRZOBDJGRNPEF-JXKHCBOESA-N 5-[3-[(2R)-2-[(E,3R,4S)-3-hydroxy-4-methyl-8-phenyloct-1-enyl]-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@H](C)[C@@H](O)\C=C\[C@@H]1N(C(=O)CC1)CCCC=1SC(=CC=1)C(O)=O)CCCC1=CC=CC=C1 ATRZOBDJGRNPEF-JXKHCBOESA-N 0.000 description 2
CRUNFNWPSSJCFB-FPQZKKRFSA-N 5-[3-[(2R)-2-[(E,3R,4S)-3-hydroxy-4-methyl-9-phenylnon-1-enyl]-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@H](C)[C@@H](O)\C=C\[C@@H]1N(C(=O)CC1)CCCC=1SC(=CC=1)C(O)=O)CCCCC1=CC=CC=C1 CRUNFNWPSSJCFB-FPQZKKRFSA-N 0.000 description 2
ZCCXWUVQGLSWPS-WSGGTOGVSA-N 5-[3-[(2R)-2-[(E,3S)-3-hydroxy-4-methyl-7-phenylhept-1-enyl]-5-oxopyrrolidin-1-yl]prop-1-ynyl]thiophene-2-carboxylic acid Chemical compound CC([C@H](O)\C=C\[C@@H]1N(C(=O)CC1)CC#CC=1SC(=CC=1)C(O)=O)CCCC1=CC=CC=C1 ZCCXWUVQGLSWPS-WSGGTOGVSA-N 0.000 description 2
UFEKCCMQUIWXBK-WSGGTOGVSA-N 5-[3-[(2R)-2-[(E,3S)-3-hydroxy-4-methyl-7-phenylhept-1-enyl]-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound CC([C@H](O)\C=C\[C@@H]1N(C(=O)CC1)CCCC=1SC(=CC=1)C(O)=O)CCCC1=CC=CC=C1 UFEKCCMQUIWXBK-WSGGTOGVSA-N 0.000 description 2
UFEKCCMQUIWXBK-URCWZONMSA-N 5-[3-[(2R)-2-[(E,3S,4R)-3-hydroxy-4-methyl-7-phenylhept-1-enyl]-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@@H](C)[C@H](O)\C=C\[C@@H]1N(C(=O)CC1)CCCC=1SC(=CC=1)C(O)=O)CCC1=CC=CC=C1 UFEKCCMQUIWXBK-URCWZONMSA-N 0.000 description 2
ATRZOBDJGRNPEF-FWILWFKNSA-N 5-[3-[(2R)-2-[(E,3S,4R)-3-hydroxy-4-methyl-8-phenyloct-1-enyl]-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@@H](C)[C@H](O)\C=C\[C@@H]1N(C(=O)CC1)CCCC=1SC(=CC=1)C(O)=O)CCCC1=CC=CC=C1 ATRZOBDJGRNPEF-FWILWFKNSA-N 0.000 description 2
ZXECFDRPIPRVFB-DPLGJEHESA-N 5-[3-[(2R)-2-[(E,3S,4S)-3-hydroxy-4-methyl-6-phenylhex-1-enyl]-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@H](C)[C@H](O)\C=C\[C@@H]1N(C(=O)CC1)CCCC=1SC(=CC=1)C(O)=O)CC1=CC=CC=C1 ZXECFDRPIPRVFB-DPLGJEHESA-N 0.000 description 2
UFEKCCMQUIWXBK-KVVBJZIMSA-N 5-[3-[(2R)-2-[(E,3S,4S)-3-hydroxy-4-methyl-7-phenylhept-1-enyl]-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@H](C)[C@H](O)\C=C\[C@@H]1N(C(=O)CC1)CCCC=1SC(=CC=1)C(O)=O)CCC1=CC=CC=C1 UFEKCCMQUIWXBK-KVVBJZIMSA-N 0.000 description 2
ATRZOBDJGRNPEF-IJTXGDDHSA-N 5-[3-[(2R)-2-[(E,3S,4S)-3-hydroxy-4-methyl-8-phenyloct-1-enyl]-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@H](C)[C@H](O)\C=C\[C@@H]1N(C(=O)CC1)CCCC=1SC(=CC=1)C(O)=O)CCCC1=CC=CC=C1 ATRZOBDJGRNPEF-IJTXGDDHSA-N 0.000 description 2
CRUNFNWPSSJCFB-QKIYNVSWSA-N 5-[3-[(2R)-2-[(E,3S,4S)-3-hydroxy-4-methyl-9-phenylnon-1-enyl]-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@H](C)[C@H](O)\C=C\[C@@H]1N(C(=O)CC1)CCCC=1SC(=CC=1)C(O)=O)CCCCC1=CC=CC=C1 CRUNFNWPSSJCFB-QKIYNVSWSA-N 0.000 description 2
QCQZBSOBEKMLKJ-MATWNZDUSA-N 5-[3-[(5R)-3,3-difluoro-5-[(E,3R)-3-hydroxyoct-1-enyl]-2-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound CCCCC[C@@H](O)\C=C\[C@H]1CC(F)(F)C(=O)N1CCCC1=CC=C(C(O)=O)S1 QCQZBSOBEKMLKJ-MATWNZDUSA-N 0.000 description 2
JMHMEEBPWHFLBX-AQLJEJBYSA-N 5-[3-[(5R)-3,3-difluoro-5-[(E,3R,4S)-3-hydroxy-4-methyl-5-phenylpent-1-enyl]-2-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@H](C)[C@@H](O)\C=C\[C@@H]1N(C(=O)C(F)(F)C1)CCCC=1SC(=CC=1)C(O)=O)C1=CC=CC=C1 JMHMEEBPWHFLBX-AQLJEJBYSA-N 0.000 description 2
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WHBBPUSLNFAUJV-MRMWBXJDSA-N 5-[3-[(5R)-3,3-difluoro-5-[(E,3R,4S)-3-hydroxy-4-phenylpent-1-enyl]-2-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@@H]1/C=C/[C@@H](O)[C@@H](C)C=2C=CC=CC=2)C(F)(F)C(=O)N1CCCC1=CC=C(C(O)=O)S1 WHBBPUSLNFAUJV-MRMWBXJDSA-N 0.000 description 2
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JP2016527117A 2013-07-19 2014-07-18 骨成長を促進するための方法、システム、及び組成物 Pending JP2016527006A (ja)

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